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Abstract:
Nonsense-mediated
mRNA
decay
(NMD)
is
a
eukaryotic
surveillance
pathway
that
degrades
aberrant
mRNAs
containing
premature
termination
codons
(PTCs).
NMD
is
triggered
upon
the
assembly
of
the
UPF
surveillance
complex
near
a
PTC.
In
humans,
UPF
assembly
is
prompted
by
the
exon
junction
complex
(EJC).
We
investigated
the
molecular
architecture
of
the
human
UPF
complex
bound
to
the
EJC
by
cryo-EM
and
using
positional
restraints
from
additional
EM,
MS
and
biochemical
interaction
data.
The
heptameric
assembly
is
built
around
UPF2,
a
scaffold
protein
with
a
ring
structure
that
closes
around
the
CH
domain
of
UPF1,
keeping
the
helicase
region
in
an
accessible
and
unwinding-competent
state.
UPF2
also
positions
UPF3
to
interact
with
the
EJC.
The
geometry
is
such
that
this
transient
complex
poises
UPF1
to
elicit
helicase
activity
toward
the
3
′
end
of
the
mRNP.
